Abstract
Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are Gαi-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.
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References
Low M (2016) Neuroendocrinology. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (eds) Williams textbook of endocrinology, 13th edn. Elsevier, Philadelphia, pp 110–176
Ben-Shlomo A, Melmed S (2010) Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 21:123–133
Taboada GF, Luque RM, Neto LV, Machado Ede O, Sbaffi BC, Domingues RC, Marcondes JB, Chimelli LM, Fontes R, Niemeyer P, de Carvalho DP, Kineman RD, Gadelha MR (2008) Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol 158:295–303
Kiseljak-Vassiliades K, Xu M, Mills TS, Smith EE, Silveira LJ, Lillehei KO, Kerr JM, Kleinschmidt-DeMasters BK, Wierman ME (2015) Differential somatostatin receptor (SSTR) 1–5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors. Mol Cell Endocrinol 417:73–83
Patel YC (1999) Somatostatin and its receptor family. Front Neuroendocrinol 20:157–198
Cervia D, Bagnoli P (2007) An update on somatostatin receptor signaling in native systems and new insights on their pathophysiology. Pharmacol Ther 116:322–341
Eigler T, Ben-Shlomo A (2014) Somatostatin system: molecular mechanisms regulating anterior pituitary hormones. J Mol Endocrinol 53:R1–R19
Schlegel W, Wuarin F, Wollheim CB, Zahnd GR (1984) Somatostatin lowers the cytosolic free Ca2+ concentration in clonal rat pituitary cells (GH3 cells). Cell Calcium 5:223–236
Cervia D, Petrucci C, Bluet-Pajot MT, Epelbaum J, Bagnoli P (2002) Inhibitory control of growth hormone secretion by somatostatin in rat pituitary GC cells: sst(2) but not sst(1) receptors are coupled to inhibition of single-cell intracellular free calcium concentrations. Neuroendocrinology 76:99–110
Kwiecien R, Tseeb V, Kurchikov A, Kordon C, Hammond C (1997) Growth hormone-releasing hormone triggers pacemaker activity and persistent Ca2+ oscillations in rat somatotrophs. J Physiol 499(Pt 3):613–623
Yang SK, Parkington HC, Epelbaum J, Keating DJ, Chen C (2007) Somatostatin decreases voltage-gated Ca2+ currents in GH3 cells through activation of somatostatin receptor 2. Am J Physiol Endocrinol Metab 292:E1863–E1870
Chen C, Clarke IJ (1996) G(o)-2 protein mediates the reduction in Ca2+ currents by somatostatin in cultured ovine somatotrophs. J Physiol 491(Pt 1):21–29
Petrucci C, Cervia D, Buzzi M, Biondi C, Bagnoli P (2000) Somatostatin-induced control of cytosolic free calcium in pituitary tumour cells. Br J Pharmacol 129:471–484
Chen ZP, Xu S, Lightman SL, Hall L, Levy A (1997) Intracellular calcium ion responses to somatostatin in cells from human somatotroph adenomas. Clin Endocrinol (Oxf) 46:45–53
Castano JP, Torronteras R, Ramirez JL, Gribouval A, Sanchez-Hormigo A, Ruiz-Navarro A, Gracia-Navarro F (1996) Somatostatin increases growth hormone (GH) secretion in a subpopulation of porcine somatotropes: evidence for functional and morphological heterogeneity among porcine GH-producing cells. Endocrinology 137:129–136
Ramirez JL, Gracia-Navarro F, Garcia-Navarro S, Torronteras R, Malagon MM, Castano JP (2002) Somatostatin stimulates GH secretion in two porcine somatotrope subpopulations through a cAMP-dependent pathway. Endocrinology 143:889–897
Tentler JJ, Hadcock JR, Gutierrez-Hartmann A (1997) Somatostatin acts by inhibiting the cyclic 3′,5′-adenosine monophosphate (cAMP)/protein kinase A pathway, cAMP response element-binding protein (CREB) phosphorylation, and CREB transcription potency. Mol Endocrinol 11:859–866
Ben-Shlomo A, Pichurin O, Khalafi R, Zhou C, Chesnokova V, Ren SG, Liu NA, Melmed S (2013) Constitutive somatostatin receptor subtype 2 activity attenuates GH synthesis. Endocrinology 154:2399–2409
Eigler T, Ben-Shlomo A, Zhou C, Khalafi R, Ren SG, Melmed S (2014) Constitutive somatostatin receptor subtype-3 signaling suppresses growth hormone synthesis. Mol Endocrinol 28:554–564
Peverelli E, Busnelli M, Vitali E, Giardino E, Gales C, Lania AG, Beck-Peccoz P, Chini B, Mantovani G, Spada A (2013) Specific roles of G(i) protein family members revealed by dissecting SST5 coupling in human pituitary cells. J Cell Sci 126:638–644
Takano K, Yasufuku-Takano J, Teramoto A, Fujita T (1997) Gi3 mediates somatostatin-induced activation of an inwardly rectifying K+ current in human growth hormone-secreting adenoma cells. Endocrinology 138:2405–2409
Sims SM, Lussier BT, Kraicer J (1991) Somatostatin activates an inwardly rectifying K+ conductance in freshly dispersed rat somatotrophs. J Physiol 441:615–637
Yang SK, Parkington HC, Blake AD, Keating DJ, Chen C (2005) Somatostatin increases voltage-gated K+ currents in GH3 cells through activation of multiple somatostatin receptors. Endocrinology 146:4975–4984
White RE, Schonbrunn A, Armstrong DL (1991) Somatostatin stimulates Ca(2+)-activated K+ channels through protein dephosphorylation. Nature 351:570–573
Hubina E, Nanzer AM, Hanson MR, Ciccarelli E, Losa M, Gaia D, Papotti M, Terreni MR, Khalaf S, Jordan S, Czirjak S, Hanzely Z, Nagy GM, Goth MI, Grossman AB, Korbonits M (2006) Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur J Endocrinol 155:371–379
Cervia D, Fiorini S, Pavan B, Biondi C, Bagnoli P (2002) Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release. Naunyn Schmiedebergs Arch Pharmacol 365:200–209
Florio T, Thellung S, Corsaro A, Bocca L, Arena S, Pattarozzi A, Villa V, Massa A, Diana F, Schettini D, Barbieri F, Ravetti JL, Spaziante R, Giusti M, Schettini G (2003) Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH-secreting pituitary adenoma cells in vitro. Clin Endocrinol (Oxf) 59:115–128
Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, Pagotto U, Stalla GK (2006) Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res 66:1576–1582
Ferrante E, Pellegrini C, Bondioni S, Peverelli E, Locatelli M, Gelmini P, Luciani P, Peri A, Mantovani G, Bosari S, Beck-Peccoz P, Spada A, Lania A (2006) Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer 13:955–962
Cuevas-Ramos D, Fleseriu M (2014) Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 52:R223–R240
Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, Alafuzoff I, Bollerslev J (2013) Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab 98:E1730–E1739
Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, de Jong T, Minuto F, Colao A, Lamberts SW, Hofland LJ (2008) Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 93:1412–1417
Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, Pronin V, Raverot G, Shimon I, Lievre KK, Fleck J, Aout M, Pedroncelli AM, Colao A, Pasireotide CSG (2014) Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol 2:875–884
Bronstein MD, Fleseriu M, Neggers S, Colao A, Sheppard M, Gu F, Shen CC, Gadelha M, Farrall AJ, Hermosillo Resendiz K, Ruffin M, Chen Y, Freda P, Pasireotide CSG (2016) Switching patients with acromegaly from octreotide to pasireotide improves biochemical control: crossover extension to a randomized, double-blind, Phase III study. BMC Endocrine Disorders 16:16
Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Culler MD, degli Uberti EC (2003) Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. J Clin Endocrinol Metab 88:2797–2802
Matrone C, Pivonello R, Colao A, Cappabianca P, Cavallo LM, Del Basso De Caro ML, Taylor JE, Culler MD, Lombardi G, Di Renzo GF, Annunziato L (2004) Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs. Neuroendocrinology 79:142–148
Ballare E, Persani L, Lania AG, Filopanti M, Giammona E, Corbetta S, Mantovani S, Arosio M, Beck-Peccoz P, Faglia G, Spada A (2001) Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab 86:3809–3814
Filopanti M, Ronchi C, Ballare E, Bondioni S, Lania AG, Losa M, Gelmini S, Peri A, Orlando C, Beck-Peccoz P, Spada A (2005) Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly. J Clin Endocrinol Metab 90:4824–4828
Ciganoka D, Balcere I, Kapa I, Peculis R, Valtere A, Nikitina-Zake L, Lase I, Schioth HB, Pirags V, Klovins J (2011) Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly. Eur J Endocrinol 165:517–525
Duran-Prado M, Gahete MD, Martinez-Fuentes AJ, Luque RM, Quintero A, Webb SM, Benito-Lopez P, Leal A, Schulz S, Gracia-Navarro F, Malagon MM, Castano JP (2009) Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J Clin Endocrinol Metab 94:2634–2643
Cordoba-Chacon J, Gahete MD, Duran-Prado M, Pozo-Salas AI, Malagon MM, Gracia-Navarro F, Kineman RD, Luque RM, Castano JP (2010) Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents. Cellular and molecular life sciences: CMLS 67:1147–1163
Luque RM, Ibanez-Costa A, Neto LV, Taboada GF, Hormaechea-Agulla D, Kasuki L, Venegas-Moreno E, Moreno-Carazo A, Galvez MA, Soto-Moreno A, Kineman RD, Culler MD, Gahete MD, Gadelha MR, Castano JP (2015) Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Lett 359:299–306
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225
Caron MG, Beaulieu M, Raymond V, Gagne B, Drouin J, Lefkowitz RJ, Labrie F (1978) Dopaminergic receptors in the anterior pituitary gland. Correlation of [3H]dihydroergocryptine binding with the dopaminergic control of prolactin release. J Biol Chem 253:2244–2253
Munemura M, Cote TE, Tsuruta K, Eskay RL, Kebabian JW (1980) The dopamine receptor in the intermediate lobe of the rat pituitary gland: pharmacological characterization. Endocrinology 107:1676–1683
Neto LV, Machado Ede O, Luque RM, Taboada GF, Marcondes JB, Chimelli LM, Quintella LP, Niemeyer P Jr, de Carvalho DP, Kineman RD, Gadelha MR (2009) Expression analysis of dopamine receptor subtypes in normal human pituitaries, nonfunctioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J Clin Endocrinol Metab 94:1931–1937
Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358:149–152
De Camilli P, Macconi D, Spada A (1979) Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas. Nature 278:252–254
Ingraham HA, Chen RP, Mangalam HJ, Elsholtz HP, Flynn SE, Lin CR, Simmons DM, Swanson L, Rosenfeld MG (1988) A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55:519–529
Elsholtz HP, Lew AM, Albert PR, Sundmark VC (1991) Inhibitory control of prolactin and Pit-1 gene promoters by dopamine. Dual signaling pathways required for D2 receptor-regulated expression of the prolactin gene. J Biol Chem 266:22919–22925
Liu YF, Civelli O, Zhou QY, Albert PR (1992) Cholera toxin-sensitive 3′,5′-cyclic adenosine monophosphate and calcium signals of the human dopamine-D1 receptor: selective potentiation by protein kinase A. Mol Endocrinol 6:1815–1824
Ferone D, Saveanu A, Culler MD, Arvigo M, Rebora A, Gatto F, Minuto F, Jaquet P (2007) Novel chimeric somatostatin analogs: facts and perspectives. Eur J Endocrinol 156(Suppl 1):S23–S28
Marazuela M, Ramos-Levi A, Sampedro-Nunez M, Bernabeu I (2014) Cabergoline treatment in acromegaly: pros. Endocrine 46:215–219
Kasuki L, Vieira Neto L, Gadelha MR (2014) Cabergoline treatment in acromegaly: cons. Endocrine 46:220–225
Saveanu A, Gunz G, Guillen S, Dufour H, Culler MD, Jaquet P (2006) Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas. Neuroendocrinology 83:258–263
Melmed S (2016) New therapeutic agents for acromegaly. Nature Rev Endocrinol 12:90–98
Day R, Dong W, Panetta R, Kraicer J, Greenwood MT, Patel YC (1995) Expression of mRNA for somatostatin receptor (sstr) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis. Endocrinology 136:5232–5235
Kumar U, Laird D, Srikant CB, Escher E, Patel YC (1997) Expression of the five somatostatin receptor (SSTR1-5) subtypes in rat pituitary somatotrophes: quantitative analysis by double-layer immunofluorescence confocal microscopy. Endocrinology 138:4473–4476
Mezey E, Hunyady B, Mitra S, Hayes E, Liu Q, Schaeffer J, Schonbrunn A (1998) Cell specific expression of the sst2A and sst5 somatostatin receptors in the rat anterior pituitary. Endocrinology 139:414–419
Bruno JF, Xu Y, Berelowitz M (1994) Somatostatin regulates somatostatin receptor subtype mRNA expression in GH3 cells. Biochem Biophys Res Commun 202:1738–1743
Greenman Y, Melmed S (1994) Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 78:398–403
Greenman Y, Melmed S (1994) Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 79:724–729
Miller GM, Alexander JM, Bikkal HA, Katznelson L, Zervas NT, Klibanski A (1995) Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 80:1386–1392
Murabe H, Shimatsu A, Ihara C, Mizuta H, Nakamura Y, Nagata I, Kikuchi H, Nakao K (1996) Expression of somatostatin receptor (SSTR) subtypes in pituitary adenomas: quantitative analysis of SSTR2 mRNA by reverse transcription-polymerase chain reaction. J Neuroendocrinol 8:605–610
Schaer JC, Waser B, Mengod G, Reubi JC (1997) Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography. Int J Cancer 70:530–537
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Ben-Shlomo, A., Liu, NA. & Melmed, S. Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas. Pituitary 20, 93–99 (2017). https://doi.org/10.1007/s11102-016-0778-2
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DOI: https://doi.org/10.1007/s11102-016-0778-2